Project Summary/Abstract Trauma and Surgical Sepsis are among the leading causes of morbidity and death worldwide. Both of these acute insults can lead to immune dysfunction that then contributes to a state of persistent critical illness. This immune dysfunction is manifested by an excessive systemic inflammatory response that can lead to organ dysfunction; and a simultaneous suppression of immune defenses that renders patients susceptible to secondary infections. Our understanding of the mechanisms that activate and propagate these responses is far from complete. The many failed clinical trials targeting the immune response in sepsis stand as testament to the importance of understanding the mechanisms that regulate the immune response to trauma and sepsis. Our strategy utilizes state-of-the-art models and techniques to interrogate the ?immunology? of trauma and sepsis at the mechanistic level. Over the next five years, we will pursue three inter-related strategies. First, we will translate basic science discoveries into our mechanistic mouse models of sepsis and trauma. We will focus on aspects of the immune response to trauma and sepsis that overlap between humans and mice. Fundamental discoveries in the field of immunology are emerging faster than ever before. We will focus attention on understanding how these discoveries relate to the integrated host immune response to sepsis and multi-system trauma. Second, we will ?reverse translate? discoveries made in critically ill humans (including those from our own extensive human trauma database and biobank) into our animal models to understand the mechanistic implications of the observations made in humans. Third, we will test agents that modify promising therapeutic targets in our models to acquire proof-of-concept insight into the translatability of our mechanistic research. Plans for the next 5 years begin with three specific goals. (1) We will establish an integrated view of the role of endotoxin (LPS) sensing pathways in the immune response to poly-microbial, intra-abdominal sepsis. To do this we will incorporate recent discoveries on Caspase-11 (Caspase-4/5 in humans), a recently described intracellular LPS receptor, into studies on the host response to intra-abdominal sepsis. We postulate that High Mobility Group Box 1 (HMGB1) will play a major role both up- and down-stream of Caspase -11 in sepsis. (2) We will define the role of the IL-33 - innate lymphocyte cell group 2 (ILC2) axis in the type 2 immune response that is known to be part of trauma- induced immune dysfunction. We have exciting preliminary data that IL-33 levels correlate with type 2 cytokine levels in humans within the first 24 h after injury. (3) We will test the efficacy of soluble guanylyl cyclase activation as a target to modify the immune response in sepsis. Each of these areas of focus represent the ?next steps? in our ongoing translational research program. As new discoveries (including from within our own program) emerge we will be ready to ?pivot? to pursue new promising research directions. We will be especially sensitive to discoveries that inform us on how to optimize our pre-clinical models.